Table Of ContentEvidence based protocol in Neonatology 2012
Sepsis in the Newborn
Sepsis is the commonest cause of neonatal mortality; it is responsible for about 30-50% of the total
neonatal deaths in developing countries.1,2 It is estimated that up to 20% of neonates develop sepsis
and approximately 1% die of sepsis related causes.2 Sepsis related mortality is largely preventable
with prevention of sepsis itself, timely recognition, rational antimicrobial therapy and aggressive
supportive care.
Epidemiology: Indian data
The incidence of neonatal sepsis according to the data from National Neonatal Perinatal Database
(NNPD, 2002-03) is 30 per 1000 live births. The NNPD network comprising of 18 tertiary care
neonatal units across India found sepsis to be one of the commonest causes of neonatal mortality
contributing to 19% of all neonatal deaths3.
Among intramural births, Klebsiella pneumoniae was the most frequently isolated pathogen
(32.5%), followed by Staphylococcus aureus (13.6%). Among extramural neonates (referred from
community/other hospitals), Klebsiella pneumoniae was again the commonest organism (27%),
followed by Staphylococcus aureus (15%) and Pseudomonas (13%).3
Definition
Neonatal sepsis is a clinical syndrome characterized by signs and symptoms of infection with or
without accompanying bacteremia in the first month of life. It encompasses various systemic
infections of the newborn such as septicemia, meningitis, pneumonia, arthritis, osteomyelitis, and
urinary tract infections.
Superficial infections like conjunctivitis and oral thrush are not usually included under neonatal
sepsis.
Classification of neonatal sepsis
Neonatal sepsis can be classified into two major categories depending up on the onset of
symptoms:4
Early onset sepsis (EOS): It presents within the first 72 hours of life. In severe cases, the neonate
may be symptomatic at birth. Infants with EOS usually present with respiratory distress and
pneumonia. The source of infection is generally the maternal genital tract. Some maternal/ perinatal
conditions have been associated with an increased risk of EOS. Knowledge about these potential risk
factors would help in early diagnosis of sepsis.
Based on the studies from India, the following risk factors seem to be associated with an increased
risk of early onset sepsis:4, 5
1. Low birth weight (<2500 grams) or prematurity
2. Febrile illness in the mother with evidence of bacterial infection within 2 weeks prior to
delivery
3. Foul smelling and/or meconium stained liquor
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
4. Rupture of membranes >24 hours
5. Single unclean or > 3 sterile vaginal examination(s) during labor
6. Prolonged labor (sum of 1st and 2nd stage of labor > 24 hrs)
7. Perinatal asphyxia (Apgar score <4 at 1 minute)
Presence of foul smelling liquor or three of the above mentioned risk factors warrant initiation of
antibiotic treatment. Infants with two risk factors should be investigated and then treated
accordingly.
Late onset sepsis (LOS): It usually presents after 72 hours of age. The source of infection in LOS is
either nosocomial (hospital-acquired) or community-acquired and neonates usually present with
septicemia, pneumonia or meningitis.6,7 Various factors that predispose to an increased risk of
nosocomial sepsis include low birth weight, prematurity, admission in intensive care unit,
mechanical ventilation, invasive procedures, administration of parenteral fluids, and use of stock
solutions.
Factors that might increase the risk of community-acquired LOS include poor hygiene, poor cord
care, bottle-feeding, and prelacteal feeds. In contrast, breastfeeding helps in prevention of
infections.
Clinical features
Non-specific features: The earliest signs of sepsis are often subtle and nonspecific; indeed, a high
index of suspicion is needed for early diagnosis. Neonates with sepsis may present with one or more
of the following symptoms and signs (a) Hypothermia or fever (former is more common in preterm
low birth weight infants) (b) Lethargy, poor cry, refusal to suck (c) Poor perfusion, prolonged
capillary refill time (d) Hypotonia, absent neonatal reflexes (e) Brady/tachycardia (f) Respiratory
distress, apnea and gasping respiration (g) Hypo/hyperglycemia (h) Metabolic acidosis.
Specific features related to various systems:
Central nervous system (CNS): Bulging anterior fontanelle, vacant stare, high-pitched cry, excess
irritability, stupor/coma, seizures, neck retraction. Presence of these features
should raise a clinical suspicion of meningitis
Cardiac: Hypotension, poor perfusion, shock
Gastrointestinal: Feed intolerance, vomiting, diarrhea, abdominal distension, paralytic ileus,
necrotizing enterocolitis (NEC)
Hepatic: Hepatomegaly, direct hyperbilirubinemia (especially with urinary tract
infections)
Renal: Acute renal failure
Hematological: Bleeding, petechiae, purpura
Skin changes: Multiple pustules, abscess, sclerema, mottling, umbilical redness and
discharge.
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
Investigations
Since treatment should be initiated in a neonate suspected to have sepsis without any delay, only
minimal and rapid investigations should be undertaken8.
Blood culture: It is the gold standard for diagnosis of septicemia and should be performed in all
cases of suspected sepsis prior to starting antibiotics. A positive blood culture with sensitivity of the
isolated organism is the best guide to antimicrobial therapy. Therefore it is very important to follow
the proper procedure for collecting a blood culture.
The resident doctor/staff should wear sterile gloves prior to the procedure and prepare a patch of
skin approximately 5 cm in diameter over the proposed veni-puncture site. This area should be
cleansed thoroughly with 70% isopropyl alcohol, followed by povidone-iodine, and followed again
by alcohol. Povidone-iodine should be applied in concentric circles moving outward from the centre.
The skin should be allowed to dry for at least 1 minute before the sample is collected.
One-mL sample of blood should be adequate for a blood culture bottle containing 5-10 mL of
culture media. Since samples collected from indwelling lines and catheters are likely to be
contaminated, cultures should be collected only from a fresh veni-puncture site. All blood cultures
should be observed for at least 72 hours before they are reported as sterile. It is now possible to
detect bacterial growth within 12-24 hours by using improved bacteriological techniques such as
BACTEC and BACT/ALERT blood culture systems. These advanced techniques can detect bacteria at a
concentration of 1-2 colony-forming unit (cfu) per mL.
Septic screen9,10: All neonates suspected to have sepsis should have a septic screen to corroborate
the diagnosis. However, the decision to start antibiotics need not be conditional to the sepsis screen
result, if there is a strong clinical suspicion of sepsis.
The various components of the septic screen include total leukocyte count (TLC), absolute
neutrophil count (ANC), immature to total (IT) neutrophil ratio, micro-erythrocyte sedimentation
rate and C reactive protein (CRP) (Table 1).
Table 1: A practical sepsis screen
Components Abnormal value
Total leukocyte count <5000/mm3
Absolute neutrophil count Low counts as per Manroe chart11 for term and
Mouzinho’s chart12 for VLBW infants
Immature/total neutrophil >0.2
Micro-ESR >15 mm in 1st hour
C reactive protein (CRP) >1 mg/dl
(ESR, erythrocyte sedimentation rate)
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
The ANC varies considerably in the immediate neonatal period and the normal reference ranges are
available from Manroe’s charts.11 The lower limit for normal ANC begins at 1800/cmm at birth, rises
to 7200/cmm at 12 hours of age and then declines and persists at 1800/cmm after 72 hours of age.
For very low birth weight infants, the reference ranges are available from Mouzinho’s charts.12 The
I/T ratio is 0.16 at birth and declines to a peak value of 0.12 after 72 hours of age.
Presence of two abnormal parameters in a screen is associated with a sensitivity of 93-100%,
specificity of 83%, positive and negative predictive values of 27% and 100% respectively in detecting
sepsis. Hence, if two (or more) parameters are abnormal, it should be considered as a positive
screen and the neonate should be started on antibiotics. If the screen is negative but clinical
suspicion persists, it should be repeated within 12 hours. If the screen is still negative, sepsis can be
excluded with reasonable certainty.
Lumbar puncture (LP): The incidence of meningitis in neonatal sepsis has varied from 0.3-3% in
various studies.3,6 The clinical features of septicemia and meningitis often overlap; it is quite
possible to have meningitis along with septicemia without any specific symptomatology. This
justifies the extra precaution of performing LP in neonates suspected to have sepsis.
In EOS, lumbar puncture is indicated in the presence of a positive blood culture or if the clinical
picture is consistent with septicemia. It is not indicated if antibiotics have been started solely due to
the presence of risk factors. In situations of late onset sepsis, LP should be done in all infants prior to
starting antibiotics.
Lumbar puncture could be postponed in a critically sick neonate. It should be performed once the
clinical condition stabilizes. The cerebrospinal fluid characteristics are unique in the newborn period
and normal values are given in Table 2.13
Table 2: Normal cerebrospinal fluid examination in neonates13
CSF Components Normal range
Cells/mm3 8 (0-30 cells)
PMN (%) 60%
CSF protein (mg/dL) 90 (20-170)
CSF glucose (mg/dL) 52 (34-119)
CSF/ blood glucose (%) 51 (44-248)
(PMN, polymorphonuclear cells; CSF, cerebrospinal fluid)
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
Radiology: Chest x-ray should be considered in the presence of respiratory distress or apnea. An
abdominal x-ray is indicated in the presence of abdominal signs suggestive of necrotizing
enterocolitis (NEC). Neurosonogram and computed tomography (CT scan) should be performed in
all patients diagnosed to have meningitis.
Urine culture: urine cultures have a low yield and are not indicated routinely. However, neonates at
risk for fungal sepsis, with urogenital malformation or vesicoureteral reflex or suspected of UTI
(crying during micturition) should have a urine examination done to exclude urinary tract infection
(UTI). Urine cultures obtained by suprapubic puncture, bladder catheterization or clean catch
sample from midstream of urine.
UTI may be diagnosed in the presence of one of the following: (a) >10 WBC/mm3 in a 10 mL
centrifuged sample (b) >104 organisms/mL in urine obtained by catheterization and (c) any organism
in urine obtained by suprapubic aspiration
Management
Supportive: Adequate and proper supportive care is crucial in a sick neonate with sepsis. He/she
should be nursed in a thermo-neutral environment taking care to avoid hypo/hyperthermia. Oxygen
saturation should be maintained in the normal range; mechanical ventilation may have to be
initiated if necessary. If the infant is hemodynamically unstable, intravenous fluids should be
administered and the infant is to be monitored for hypo/hyperglycemia. Volume expansion with
crystalloids/colloids and judicious use of inotropes are essential to maintain normal tissue perfusion
and blood pressure. Packed red cells and fresh frozen plasma might have to be used in the event of
anemia or bleeding diathesis.
Antimicrobial therapy: There cannot be a single recommendation for the antibiotic regimen of
neonatal sepsis for all settings. The choice of antibiotics depends on the prevailing flora in the given
unit and their antimicrobial sensitivity. This protocol does not aim to provide a universal
recommendation for all settings but lays down broad guidelines for the providers to make a rational
choice of antibiotic combination. Decision to start antibiotics is based upon clinical features and/ or
a positive septic screen. However duration of antibiotic therapy is dependent upon the presence of
a positive blood culture and meningitis (Table 3).
Table 3. Duration of antibiotic therapy in neonatal sepsis
Diagnosis Duration
Meningitis (with or without positive blood/CSF culture) 21 days
Blood culture positive but no meningitis 14 days
Culture negative sepsis (screen positive and clinical 5-7 days
course consistent with sepsis)
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
Indications for starting antibiotics: The indications for starting antibiotics in neonates at risk of EOS
include any one of the following:
(a) presence of >3 risk factors for early onset sepsis (see above)
(b) presence of foul smelling liquor
(c) presence of 2 antenatal risk factor(s) and a positive septic screen and
(d) strong clinical suspicion of sepsis.
The indications for starting antibiotics in LOS include:
(a) positive septic screen and/or
(b) strong clinical suspicion of sepsis.
Prophylactic antibiotics: We do not use prophylactic antibiotics in the following circumstances:
infants on IV fluids/TPN, meconium aspiration syndrome, and after exchange transfusion(s). An
exchange transfusion conducted under strict asepsis (single use catheter, sterile gloves, removal of
catheter after the procedure) does not increase the risk of sepsis and hence does not merit
antibiotics. However a messy exchange transfusion could be treated with prophylactic antibiotics.
Choice of antibiotics: Empirical antibiotic therapy should be unit-specific and determined by the
prevalent spectrum of etiological agents and their antibiotic sensitivity pattern. Antibiotics once
started should be modified according to the sensitivity reports. Guidelines for empirical antibiotic
therapy have been provided in Table 4.
Table 4. Empirical choice of antibiotics for treatment of neonatal sepsis
Clinical situation Septicemia & Meningitis
Pneumonia
FIRST LINE Penicillin or Ampicillin Add Cefotaxime
Community-acquired and
(Resistant strains unlikely) Gentamicin
SECOND LINE Ampicillin or Cloxacillin Add Cefotaxime
Hospital-acquired and
Some strains are likely to be Gentamicin or Amikacin
resistant
THIRD LINE Cefotaxime or
Piperacillin-Tazobactam or
Ciprofloxacin Same (Avoid Cipro)
Hospital-acquired sepsis and
(Most strains are Amikacin;
Likely to be resistant)
Consider Vancomycin if MRSA is suspected.
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
The empirical choice of antibiotics is dependent upon the probable source of infection. For
infections that are likely to be community-acquired where resistant strains are unlikely, a
combination of ampicillin or penicillin with gentamicin may be a good choice as a first line therapy.
For infections that are acquired during hospital stay, resistant pathogens are likely and a
combination of ampicillin or cloxacillin with gentamicin or amikacin may be instituted. In nurseries
where this combination is ineffective due to the presence of multiple resistant strains of klebsiella
and other gram-negative bacilli, a combination of a third generation cephalosporin (cefotaxime or
ceftazidime) with amikacin may be appropriate. 3rd generation cephalosporins have very good CSF
penetration and are traditionally thought to have excellent antimicrobial activity against gram
negative organisms. Hence they were considered to be a good choice for the treatment of
nosocomial infections and meningitis. However, recent reports suggest that at least 60-70% of the
Gram-ve organisms are resistant to them.14-16 More over, routine use of these antibiotics might
increase the risk of infections with ESBL (extended spectrum beta-lactamase) positive organisms.
Therefore it is preferable to use antibiotics such as piperacillin-tazobactam or
methicillin/vancomycin in units with high incidence of resistant strains.
A combination of piperacillin-tazobactam with amikacin should be considered if pseudomonas
sepsis is suspected. Penicillin resistant staphylococcus aureus should be treated with cloxacillin,
nafcillin or methicillin. Addition of an aminoglycoside is useful in therapy against staphylococcus.
Methicillin resistant staphylococcus aureus (MRSA) should be treated with a combination of
ciprofloxacin or vancomycin with amikacin. Ciprofloxacin has excellent activity against gram-
negative organisms also; however, it does not have good CSF penetration. It may be used for the
treatment of resistant gram-negative bacteremia after excluding meningitis.
For sepsis due to enterococcus, a combination of ampicillin and gentamicin is a good choice for
initial therapy. Vancomycin should be used for the treatment of enterococcus resistant to the first
line of therapy.
The dosage, route, and frequency of commonly used antibiotics are given in Table 5.
Reserve antibiotics: Newer antibiotics like aztreonam, meropenem and imipenem are also now
available in the market. Aztreonam has excellent activity against gram-negative organisms while
meropenem is effective against most bacterial pathogens except methicillin resistant
staphylococcus aureus (MRSA) and enterococcus. Imipenem is generally avoided in neonates
because of the reported increase in the incidence of seizures following its use. Empirical use of these
antibiotics should be avoided; they should be reserved for situations where sensitivity of the
isolated organism warrants its use.
Adjunctive therapy
Exchange transfusion (ET): Sadana et al17 have evaluated the role of double volume exchange
transfusion in septic neonates with sclerema and demonstrated a 50% reduction in sepsis related
mortality in the treated group. We perform double-volume exchange transfusion with cross-
matched fresh whole blood as adjunctive therapy in septic neonates with sclerema.
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
Intravenous Immunoglobulin (IVIG): Non-specific pooled IVIG has not been found to be useful.18
Granulocyte-Macrophage colony stimulating factor (GM-CSF): This mode of treatment is still
experimental.19
Table 5. Drugs, route of administration and doses of common antibiotics used.
Drug Route Birth Weight 2000g Birth Weight >2000g
0-7 d >7 days 0-7 days >7 days
Amikacin I/V, I/M 7.5 q12h 7.5 q8h 10 q12h 10 q8h
Ampicillin
Meningitis I/V 100 q12h 100 q8h 100 q 8h 100 q6h
Others I/V, I/M 25 q12h 25 q8h 25 q8h 25 q6h
Cefotoxime
Meningitis I/V 50 q6h 50 q6h 50 q6h 50 q6h
Others I/M, I/V 50 q12h 50 q8h 50 q12h 50 q8h
Piperacillin+ I/V 50-100 q12h 50-100 q8h 50-100 q12h 50-100 q12h
Tazobactam
Ceftriaxone I/M, I/V 50 q24h 50 q24h 50 q24h 75 q24h
Ciprofloxacin I/V, PO 10-20 q24h 10-20 q24h 10-20 q12h 10-20 q12h
Cloxacillin
Meningitis I/V 50 q12h 50 q8h 50 q8h 50 q6h
Others I/V 25 q12h 25 q8h 25 q8h 25 q6h
Gentamicin
Conventional I/V, I/M 2.5 q12h 2.5 q8h 2.5 q12h 2.5 q8h
Single dose I/M 4 q24 h 4 q24 hr 5 q24h 5 q24h
Netilmicin I/V, I/M 2.5 q12h 2.5 q8h 2.5 q12h 2.5 q8h
Penicillin G (units/kg/dose)
Meningitis I/V 75,000 q12h 75,000 q8h 75,000 q8h 75,000 q6h
-100,000 -1,00,000 -1,00,000 -1,00,000
Others I/V, I/M 25,000 q12h 25,000 q8h 25,000 q8h 25,000 q6h
Vancomycin I/V 15 q12h 15 q8h 15 q12h 15 q8h
All doses are in mg/kg/dose; (I/V, intravenous; I/M, intramuscular; PO, per-oral; h, hourly)
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
AIIMS WHO-CC
Evidence based protocol in Neonatology 2012
Table 7 : Research questions pertaining to neonatal sepsis
Research question Subjects Study Interven Outcomes to
design tion be measured
1. Does antimicrobial All Before and Bundle The incidence
stewardship (AMS) babies after study of of health care
reduce the rates of admitted intervent associated
health care to NICU ions to infections,
associated infections constitut neonatal
in NICU? e AMS: mortality
2.What is the rate of All Retrospectiv None Rates of
medication errors babies e study medication
with regard to admitted errors and
antibiotic prescripti- to NICU estimated
on in a level II NICU? in the additional costs
last two due to it
years
3. What are the All Descriptive None The rates of
trends of de- babies study de-escalation
escalating from admitted of therapy and
broad-spectrum to NICU incidence of
combination therapy and infections/mor
to directed therapy receiving bidities after
and the rates of antibioti antibiotic
relapse of infection cs change
in those undergoing
this de-escalation?
4. What is the culture All Descriptive None The rate of
positivity rates in babies study blood, CSF and
babies previously born in (stratified by other fluids
exposed with the birth culture
antibiotics? hospital weight/gest
to ational age)
mothers
with
prior
antibioti
c
exposur
e
5. What is the All Descriptive None The costs of
antimicro-bial babies both out of
expenditu-re(both receiving pocket and
out of pocket and antibioti hospital supply
hospital supply) and cs in antibiotic per
trends over time? NICU baby receiving
antibiotics
AIIMS WHO-CC
Description:Evidence based protocol in Neonatology 2012 AIIMS WHO-CC Sepsis in the Newborn Sepsis is the commonest cause of neonatal mortality; it is responsible for about 30-50%
